Millimaki, Bonny Butler (2010-08). The Function and Genetic Interactions of Zebrafish atoh1 and sox2: Genes Involved in Hair Cell Development and Regeneration. Doctoral Dissertation. Thesis uri icon

abstract

  • The sensory cells of the inner ear, hair cells, provide vertebrates with the ability to detect auditory stimuli and balance. In mammals, cochlear hair cells, those responsible for hearing, do not regenerate. Zebrafish hair cells do regenerate. Gaining an understanding of the role and regulation of the genes involved in the formation and regeneration of these cells may provide information important for the development of genetic therapies. We show that zebrafish atoh1 acts as the proneural gene responsible for defining the equivalence group from which hair cells form. Expression of atoh1 is dependent upon Fgf and Pax. Atoh1 induces expression of delta, resulting in activation of Notch and subsequent lateral inhibition. Another factor known to be important for hair cell formation in mice is Sox2. In zebrafish, sox2 expression is downstream of Atoh1, Notch and Fgf. Zebrafish Sox2 is not required for hair cell formation, but rather Sox2 is important for hair cell maintenance. In zebrafish, otic hair cell regeneration has not yet been characterized. We show that, following laser ablation, hair cells regenerate by way of transdifferentiation. We further show that this regeneration requires Sox2 activity. These data suggest that Sox2 acts to maintain support cell plasticity. This role is likely conserved because Sox2 is also important for stem cell plasticity in mammals. This new understanding of the role and regulation of both Atoh1 and Sox2 provides essential information that can be used to further efforts to provide genetic therapies for hair cell regeneration in mammals.
  • The sensory cells of the inner ear, hair cells, provide vertebrates with the ability

    to detect auditory stimuli and balance. In mammals, cochlear hair cells, those

    responsible for hearing, do not regenerate. Zebrafish hair cells do regenerate. Gaining

    an understanding of the role and regulation of the genes involved in the formation and

    regeneration of these cells may provide information important for the development of

    genetic therapies.

    We show that zebrafish atoh1 acts as the proneural gene responsible for defining

    the equivalence group from which hair cells form. Expression of atoh1 is dependent

    upon Fgf and Pax. Atoh1 induces expression of delta, resulting in activation of Notch

    and subsequent lateral inhibition. Another factor known to be important for hair cell

    formation in mice is Sox2. In zebrafish, sox2 expression is downstream of Atoh1, Notch

    and Fgf. Zebrafish Sox2 is not required for hair cell formation, but rather Sox2 is

    important for hair cell maintenance.

    In zebrafish, otic hair cell regeneration has not yet been characterized. We show

    that, following laser ablation, hair cells regenerate by way of transdifferentiation. We further show that this regeneration requires Sox2 activity. These data suggest that Sox2

    acts to maintain support cell plasticity. This role is likely conserved because Sox2 is

    also important for stem cell plasticity in mammals. This new understanding of the role

    and regulation of both Atoh1 and Sox2 provides essential information that can be used to

    further efforts to provide genetic therapies for hair cell regeneration in mammals.

publication date

  • August 2010